In this renewal application for the UCSD HIV Neurobehavioral Research Center (HNRC) we propose to provide scientific expertise and infrastructure to support studies that better elucidate current theories, and develop new insights, into the mechanisms behind the development and persistence of HIV-associated neurocognitive disorders (HAND). In particular, the HNRC is positioning itself to facilitate studies addressing important new research themes, including persistence and eradication of HIV in the CNS (cure agenda) and the role of alterations in the gut microbiota as a contributor to HAND. To accomplish this we have recruited world-class investigators in these fields to the HNRC. Since studies of microbiome effects and eradication may be most informative in the earliest stages of infection and treatment, we will establish a major new partnership with UCSD's primary infection screening program, which will enrich the HNRC cohort with primary infection cases. A longitudinal cohort of HIV+ and HIV- participants, to ultimately include 100 primary infection cases, will be comprehensively examined to facilitate/enable supported studies. This renewal builds on the track record of the HNRC as a national and international leader and resource facilitating research on neuropathogenesis, treatment, and prevention of HAND. Ongoing, continuity areas of emphasis are to support studies examining a) mechanisms of aging and HIV interaction, whereby aging and HIV may interact in determining an increased occurrence, as well as possible differences in features, prognosis, and treatment challenges for neuroAIDS in older individuals, addressing the OAR priority to investigate premature aging associated with long-term HIV disease and ART, and b) clinical relevance: new treatments/biomarkers/new methods (e.g., Do new ARV and non-ARV treatments alter the development of HAND? What additional biomarkers can be identified/developed to better detect and predict HAND? How can these and other tools be translated into methods that are useful in the clinic?). To accomplish these goals, we are proposing a streamlined and better integrated organization of the HNRC into 3 scientific Cores (NeuroAssessment, NeuroGerm, and NeuroBiology) that will provide intellectual leadership and technical support, with an Administrative Core to support and coordinate their activities; and a Developmental Core, which will support innovative preliminary studies and coordinate training and mentorship with the scientific cores and HNRC-associated faculty, targeting the future generation of neuro- HIV scientists. In addition to our numerous U.S. collaborations in neuroAIDS research, the international component of the Developmental Core will provide consultation to international scholars, help translate techniques developed at the HNRC to diverse settings around the world, and support joint research efforts between U.S. and foreign investigators. With these structures and processes the HNRC will continue to foster its national and international leadership role in vital neuro-HIV research, training, and treatment.